A bibliometric analysis of research trends and hotspots regarding macrophage polarization in lung cancer

Introduction

Lung cancer is a highly heterogeneous malignant neoplasm that arises from the mucosal or glandular tissues of the trachea and bronchi. The incidence and mortality rates of this malignancy are the highest among male cancers, resulting in over 1.8 million fatalities annually and representing the primary cause of cancer-related deaths, thereby posing a significant threat to human health (1). The primary causes of lung cancer are predominantly environmental factors, including smoking and air pollution (2). These factors induce persistent mutations in lung epithelial cells, thereby facilitating the onset, progression, and metastasis of tumors. Although the treatment strategies for lung cancer have been continuously optimized over the past decade, traditional surgery, radiotherapy, chemotherapy, and targeted therapy have improved the prognosis of lung cancer patients to some extent, the overall survival rate still fails to achieve a significant increase (3).

Macrophage polarization refers to the dynamic biological process by which mature macrophages, influenced by specific microenvironmental signals, develop into functionally diverse phenotypic lineages. This process can demonstrate substantial bidirectional regulatory effects in the lung cancer microenvironment (4,5). Specifically, when macrophages are activated by immune complexes or exposed to cytokines such as interleukin (IL)-4 and IL-13 released by tumor cells, they polarize into an M2 phenotype, marked by an elevated secretion of cytokines, including IL-10 and transforming growth factor-beta (TGF-β), within the tumor microenvironment. M2 macrophages can markedly impede the influx of cytotoxic T lymphocytes into tumor tissues, while facilitating tumor-associated angiogenesis and stromal remodeling, therefore expediting the growth and spread of lung cancer (6,7). Conversely, in a microenvironment characterized by the presence of pathogen-associated molecular patterns, such as lipopolysaccharide (LPS), or when Th1-type cytokines, including interferon-gamma (IFN-γ), influence macrophages, they polarize into the M1 phenotype and significantly express pro-inflammatory molecules, including tumor necrosis factor-alpha (TNF-α), IL-12, and IL-6. M1 macrophages can substantially enhance the infiltration and anti-tumor efficacy of cytotoxic T lymphocytes, thereby impeding tumor growth and metastasis (8). Considering the spatiotemporal variability of macrophage polarization within the immune microenvironment of lung cancer and its significant influence on immune editing and evasion, a comprehensive analysis of research trends in this domain has emerged as a crucial avenue to overcome the challenges in lung cancer immunotherapy.

Bibliometrics is a quantitative approach for performing mathematical and statistical analyses of scholarly literature. Its utilisation in medicine transcends the subjectivity and disjointedness of conventional literature reviews, offering an objective framework for analyzing research trends (9). Despite extensive discourse on the regulatory significance of macrophage polarization within the immune microenvironment of lung cancer, and a yearly increase in related experiments and reviews, systematic quantitative research addressing the knowledge evolution trajectory, core strength distribution, and emerging hotspots of this subject remains uncharted territory. Therefore, this study performed a systematic bibliometric analysis and visualization of the pertinent literature on macrophage polarization in lung cancer research. It encompassed academic output and collaboration networks across various countries, institutions, authors, and journals, as well as co-occurrence, clustering, and the emergence of references and keywords. The objective is to thoroughly illustrate the knowledge framework of this domain, precisely pinpoint research hotspots and emerging frontiers, and offer insightful concepts and a strategic plan for future investigations into the mechanisms of macrophage polarization in lung cancer and clinical translational research. We present this article in accordance with the BIBLIO reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0766/rc).

Methods

Data sources and processing

This research employed the Web of Science Core Collection (WoSCC) and Scopus databases as data sources. A search strategy was developed utilizing the key terms “Macrophage polarization” and “Lung Cancer” (Tables S1,S2). The search timeframe was constrained to January 1, 2010, through August 1, 2025. To eliminate any potential deviations induced by the dynamic updates of the database, all publications were retrieved on the same day, August 1, 2025, to ensure the timeliness and reliability of the retrieved data. The search results indicated that the WoSCC database retrieved 334 documents, whereas the Scopus database retrieved 437 papers. This study excluded non-target literature types, including Meeting Abstracts, Book Chapters, Corrections, Early Access materials, Editorials, Short Surveys, and Conference Papers, retaining only Articles and Reviews published in English to ensure data comprehensiveness and consistency. After this screening, the WoSCC database discarded 20 documents, while the Scopus database removed 22 papers. To guarantee the authenticity and comprehensiveness of the final literature selection, the research team performed manual verification of the screened material and excluded any retracted papers. To prevent inaccuracies arising from varying citation versions, two independent reviewers individually retrieved raw data, and any inconsistencies were handled through consensus meetings. Following the screening process, standardized formatting was applied to the selected literature from WoSCC (N₁=313) and Scopus (N₂=414). Deduplication was performed on Scopus literature (N₂=219) using the DOIs from the WoSCC database, resulting in 508 legitimate publications after final consolidation (comprising 446 Articles and 62 Reviews). The literature screening method is depicted in full in Figure 1.

Figure 1 Article screening flow chart. DOI, digital object identifier; WoSCC, Web of Science Core Collection.

Data analysis and visualization

This study, based on the normalized integrated database of WoSCC and Scopus, utilized VOSviewer (v1.6.20), CiteSpace (v6.4.R1), and the bibliometrix package in R (v4.5.1) to systematically present the results of the bibliometric analysis (10). VOSviewer is a visualization tool created by van Eck and Waltman at Leiden University. It is extensively employed to precisely analyze and visualize intricate bibliometric relationships under high-density conditions (11). This study utilized its Co-authorship and Co-occurrence modules to construct collaboration networks for countries/regions, institutions, journals, and authors, as well as keyword co-occurrence networks. In the data processing phase, the integrated synonym database was employed to standardize and consolidate the names of countries/regions, institutions, authors, and keywords. At the same time, the attractive and repulsive force parameters were modified to improve the clarity of the graphs. In the visualization outcomes, the nodes signify entities such as countries, regions, institutions, researchers, and keywords, among others. The dimensions and hue of the nodes represent the quantity and categorization, while the thickness of the connections between nodes signifies the degree of collaboration or co-citation (12,13).

CiteSpace was collaboratively developed by Dr. Chen Chaomei and the WISE Laboratory at Dalian University of Technology. It is utilized for the multi-temporal analysis and dynamic visualization of knowledge networks (14). This study primarily used its algorithmic framework to analyze the significant phenomenon of citation explosion related to references and keywords. The evolution trends and potential research frontiers of this field can be elucidated through co-citation network diagrams, timeline graphs, time zone diagrams, and centrality calculations. Simultaneously, it is employed to produce a dual map of journals, which is subsequently overlapped to elucidate the attributes of interdisciplinary research and regional collaboration (15). The parameter optimization is established as follows: a time slicing interval of one year, a node selection threshold of g-index =25, and the implementation of Pathfinder network scaling and pruning techniques to reduce redundant connections while preserving structural integrity. This study employs R, an open-source computational programming environment, for its programming capabilities to integrate and process bibliographic records obtained from the WoSCC and Scopus databases, thereby creating a highly consistent and minimally biased analysis dataset. This study utilizes the BiblioAnalysis and H-index functions from the bibliometrix package to derive comprehensive indicators of publication output and influence for various countries, institutions, and authors, with the H-index serving as the primary metric for assessing their academic productivity and influence (16).

Statistical analysis

All bibliometric quantitative indicators were calculated via the bibliometrix package (v4.5.1) in R software. Descriptive statistical indicators included total publication count, total citations, average citations per article, H-index, total link strength (TLS), centrality, and annual publication growth rate. The exponential fitting model y = e^0.4266x was constructed to fit cumulative publication volumes from 2010 to 2025; the coefficient of determination R² was calculated to evaluate the fitting effect of the trend curve. Modularity Q and Silhouette S values generated by CiteSpace were used to judge the reliability of co-citation clustering results (Q >0.3 and S >0.7 represented significant, stable clustering structures). Citation burst strength values were extracted to identify frontier hot papers and emerging research topics. No clinical biological statistical tests (t-test, ANOVA, correlation regression etc.) were required in this bibliometric study, and all visualized network parameters were standardized with unified synonym merging to eliminate data bias caused by inconsistent keyword/author naming formats. All data collation and statistical output were double-checked by two independent researchers to reduce human error.

Results

The annual trend of paper publication quantity

This study encompasses 508 research papers authored by 3,916 researchers from 1,120 institutions across 54 countries and regions. The papers were published in 250 academic journals, garnering a total of 29,211 citations, with an average of 57.5 citations per paper. Figure 2 depicts the annual publication trends in this domain, revealing a steady increase since 2010, culminating in a peak of 131 publications by 2025. Notably, the most significant increase in publication growth occurred after 2022, with the peak annual growth rate reaching 77.1%. To quantify this trend, this study formulates an exponential growth model, y = e^0.4266x, where x represents the year and y represents the dependent variable, indicating the cumulative publication count. The coefficient of determination R² (0.9729) approaches one, signifying that this exponential curve demonstrates substantial explanatory power concerning the variation in annual cumulative publications. This finding further illustrates that the increase observed since 2022 is not a mere incidental fluctuation but rather an inevitable advancement along the established exponential trajectory.

Figure 2 Annual publication trends of literature related to macrophage polarization and lung cancer treatment from January 2010 to August 2025.

This research field concerning macrophage polarization in lung cancer can be categorized into three phases based on the growth patterns of annual and cumulative publications: the preliminary exploration phase from 2010 to 2016, characterized by an average of fewer than 20 publications annually while exhibiting stable overall growth; the steady growth phase from 2017 to 2021, during which 124 relevant publications were amassed, signifying a gradual increase in academic interest; and the remarkable development phase post-2022, with 349 cumulative publications representing 60.17% of the total output, underscoring the escalating significance of macrophage polarization in lung cancer research and its emergence as a focal point and frontier in the discipline.

Analysis of countries/regions

Table 1 systematically outlines the 10 leading countries/regions for research production in this domain. China dominates with 370 publications, accounting for over 70% of the total, which is six times the output of the second-ranked USA (n=62) and far exceeds that of other nations, such as South Korea (n=25) and India (n=15). However, the analysis of citation frequency per publication indicates that China’s average is only 20.85 citations, markedly lower than that of the USA (94.65), Japan (87.40), Spain (80.57), and Germany (56.25). This discrepancy suggests that China’s academic impact has not yet corresponded with the volume of research production. Regarding the H-index, China holds the highest H-index at 38, followed by the USA with a score of 30. All other nations register scores below 15, underscoring the academic preeminence of these two countries in this domain. Centrality measures reveal that China, with a score of 0.58, functions as a crucial nexus in the transnational collaboration network in this field, markedly exceeding the USA (0.31). This highlights China’s pivotal function as a conduit for global knowledge exchange. Moreover, as a developing nation, India (0.24) occupies the third position in centrality measures, following China and the USA, signifying its significant role as a knowledge intermediary in the macrophage polarization and lung cancer research network. This demonstrates the active incorporation of its scientific institutions into the central channels of global information transmission via frequent, high-quality international collaborations, thus gradually transcending their historically marginal position in scientific research. TLS serves as a holistic metric for evaluating the extent and intensity of international collaboration. Elevated values signify a nation’s improved ability to integrate resources and foster synergistic innovation within transnational scientific research networks (17). The metric indicates that the TLS values of China (TLS =40) and the USA (TLS =39) markedly exceed those of other countries, signifying that these two nations hold a unique advantage in assimilating international scientific research resources and spearheading transnational collaborative innovation efforts.

Figure 3 depicts the cooperative network among different nations. The results show that the intensity of scientific research collaboration between China and the USA, which has the highest volume of publications, significantly surpasses that of other country pairings. This establishes China as the central hub of the worldwide scientific research cooperation network in this domain. Moreover, scientific research collaboration between the USA and South Korea has been very vigorous, highlighting the technical complementarity and mutual strategic objectives in lung cancer and macrophage polarization research. This is especially apparent in the investigation of lung cancer microenvironment processes and the translational implementation of immunotherapy, where both entities exhibit highly synergistic research priorities and advantages in resource integration.

Figure 3 National cooperation network map.

Analysis of institutions

Table 2 systematically outlines the ten foremost institutions that have made significant contributions to the research domain of macrophage polarization in lung cancer. Fudan University tops the chart with 19 publications, followed by Chinese Academy of Medical Sciences (n=15) and Shanghai Jiao Tong University (n=14). These three institutions jointly constitute the premier tier of scientific research output in this domain, underscoring their significant academic standing. In terms of the H-index, Fudan University (H-index =11), Zhejiang University (H-index =9), and the Chinese Academy of Medical Sciences (H-index =8) rank among the top, indicating that they maintain high-quality scientific research output while demonstrating a stable academic influence. In terms of citations, Zhejiang University (38.23) and Fudan University (34.53) significantly outperform other institutions, reflecting that the research results of these two institutions have gained high recognition from international peers in terms of methodological innovation and clinical translation value. In terms of the TLS, the Chinese Academy of Medical Sciences (TLS =65) and Fudan University (TLS =62) far exceed other institutions, indicating that these two institutions have established high-density academic communities centered around themselves internationally and possess significant advantages in integrating multi-disciplinary resources and leading large-scale collaborative projects. Significantly, all ten leading contributing institutions are associated with China, demonstrating that China’s research in this domain is concentrated in premier universities and research institutes, thereby establishing a systematic and sustained advantage in knowledge generation. This has substantially advanced the research on macrophage polarization in lung cancer.

Figure 4A illustrates the collaborative network among diverse institutions. The results show that Fudan University, possessing the highest publication count, sustains strong partnerships with Shanghai Jiao Tong University and Shanghai University of Traditional Chinese Medicine. This indicates that an inter-institutional collaboration model efficiently enhances knowledge integration and the efficient distribution of research resources, hence fostering the establishment of a multi-center research paradigm. Figure 4B illustrates the average active time of different institutions in this field. In general, most institutions, exemplified by Capital Medical University, have been notably engaged in this research domain over the previous five years. This underscores that the area is undergoing rapid advancement, with fresh scientific research consistently contributing to the growth of its disciplinary boundaries.

Figure 4 Collaboration network analysis of countries/regions in macrophage polarization and lung cancer research. (A) A collaborative network diagram of publications from different institutions. (B) Time evolution chart of publications from different institutions.

Analysis of authors

Table 3 lists the ten most prolific authors based on their publication count in this domain. The results show that Wang Yi-Ching (n=5) from National Cheng Kung University in China possesses the greatest publication count. Yang Bo (n=4) from Zhejiang University in China, ranks second. Despite Yang Bo’s publication count being marginally lower than that of Wang Yi-Ching, Yang Bo’s average citation rate (88.00) surpasses that of Wang Yi-Ching (12.80), underscoring Yang Bo’s significant academic impact and individual accomplishments in this domain. Notably, 80% of the top 10 authors ranked by publication volume are affiliated with Chinese institutions, with National Cheng Kung University and Zhejiang University accounting for the largest shares. This phenomenon reaffirms the significant accumulation of these two institutions in tumor immunology platforms, scientific research resources, and international talent tiers. It also reflects their crucial position within the global knowledge network in this field from a metrological perspective. Notably, macrophage polarization in tumor research is still in its early stages, characterized by a low per capita output among leading authors and limited disciplinary advancement. Therefore, future research requires worldwide and institutional collaboration to overcome geographical and disciplinary barriers, thereby enhancing knowledge creation and clinical translation potential in this new field through synergistic innovation.

Figure 5A depicts the cooperation network among diverse authors. Overall, author clusters display robust internal collaboration, while inter-cluster relationships are notably limited, indicating a significant fragmentation phenomenon. Figure 5B depicts the mean active durations of different authors in this field. Overall, the percentage of active writers in this study domain over the last five years is notably high. Conversely, the preeminent author, Yang Bo, was active in an earlier era. This signifies that Yang, Bo’s research efforts in this domain have established a theoretical basis for subsequent investigations by other scholars.

Figure 5 Institutional and author contribution analysis in macrophage polarization and lung cancer research. (A) The collaborative network diagram between authors. (B) The time evolution chart of the author’s publication.

Analysis of journals

Figure 6A depicts the distribution patterns of journals and citation links for research on the association between lung cancer and macrophage polarization within the framework of disciplinary mapping. Among these, the left side illustrates the disciplinary distribution of citing journals, delineating the existing research landscape in the field; the right side exhibits the disciplinary background of cited journals, uncovering the theoretical underpinnings of the domain. The figure features colored curves that depict citation paths among various journals. The results show that the connection between journals in the “Molecular Biology and Genetics” domain and those in the “Molecular Biology and Immunology” domain is the most pronounced, indicating that a considerable share of research outputs from the “Molecular Biology and Genetics” domain are primarily cited within the “Molecular Biology and Immunology” domain. The concern is that the citation trajectory from “Molecular Biology, Genetics” to “Molecular Biology, Immunology” exhibits the highest Z-score (Z=6.52), highlighting the significant importance and academic impact of this knowledge flow in the field's progress. This study utilizes comprehensive data on citing and cited journals, obtained through VOSviewer, to create the citing journal coverage map (Figure 6B) and the cited journal coverage map (Figure 6C). These maps visually illustrate the specific interrelationships among these journals in a dual-map overlay format.

Figure 6 Keyword co-occurrence and research hotspot analysis. (A) Dual-map overlay analysis map. (B) Citing journals overlay. (C) Cited journals overlay.

Table 4 displays the top 10 journals rated by publication volume and citation frequency, respectively. At the publication level, Frontiers in Immunology ranked first with 25 articles, indicating that this field is a key frontier direction in current tumor immunology research. Secondly, the journals International Immunopharmacology and Advanced Science ranked second and third, with 16 and 15 publications, respectively, highlighting the considerable focus on macrophage polarization in lung cancer research within the immunology domain. In terms of citation frequency, the journal Nature Nanotechnology has the highest, with 1,299 citations, followed by the International Journal of Molecular Sciences with 1,098 citations, and Frontiers in Immunology with 1,044 citations. This indicates that the research findings disseminated in these journals have established a solid theoretical foundation for progress in the subject. In summary, despite the extensive array of journals in this domain, Frontiers in Immunology distinguishes itself by its substantial publishing output and citation frequency, signifying its elevated academic stature and reference significance in the scientific area of lung cancer and macrophage polarization.

Analysis of reference

Table 5 displays the ten papers with the highest total citation counts. Among these, the study “Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries”, authored by Sung Hyuna et al., leads with a total of 43 cited journals. It is closely followed by “A narrative review of tumor-associated macrophages in lung cancer: regulation of macrophage polarization and therapeutic implications”, authored by Sedighzadeh Sahar et al. (n=20), and “Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries”, by Bray Freddie et al. (n=16). However, the cited journals are inherently affected by the temporal accumulation effect, wherein earlier publications tend to enjoy an extended citation period, potentially exaggerating their perceived academic significance. Thus, this study mitigates temporal bias by utilizing the mean annual citation frequency as the primary statistic. The results show that the 2021 article in CA-A Cancer Journal for Clinicians, titled “Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries”, has sustained a significant average annual citation rate of 8.6. This highlights its ongoing impact on macro-level oncology research and its contribution to current epidemiological benchmarks for studies on lung cancer and macrophage polarization. Following closely, “A narrative review of tumor-associated macrophages in lung cancer: regulation of macrophage polarization and therapeutic implications” (4) was published in Translational Lung Cancer Research and International Journal of Molecular Sciences of “Macrophage polarization States in the Tumor Microenvironment” (2.8). These two articles systematically elucidate the molecular mechanisms and functional roles of M1/M2 polarization in the initiation and progression of lung cancer, providing substantial reference value for research in lung cancer and macrophage polarization.

Figure 7A depicts the co-citation network of the references. Overall, the node colors display a gradient shift from cool to warm tones, indicating the gradual emergence of new references over time. This illustrates the continuous collection and refinement of knowledge in the domain of lung cancer and macrophage polarization, thereby allowing researchers to swiftly pinpoint emerging hotspots, elucidate evolutionary pathways, and strategically devise future research trajectories. Figure 7B illustrates the clustering outcomes of co-cited literature. The study indicates a Modularity (Q) value of 0.873 (>0.3) and a Silhouette (S) value of 0.9277 (>0.7), signifying a statistically significant and robust clustering structure in the co-citation network. Subsequent analysis at the cluster level identifies three principal research themes as follows: Cluster #0 (exosomes), Cluster #1 (iron nanoparticles), and Cluster #2 (nf-kappa b). Figure 7C illustrates the 25 references with the most significant citation bursts. The results show that Sung H. [2021] holds the top position with a burst strength of 6.23. This article has garnered considerable interest in the domain of lung cancer and macrophage polarization research since its publication in 2022. The differing burst time periods in various publications indicate generational changes in research focal points. Sica A [2013], with a burst phase from 2015 to 2017, and Pyonteck SM [2012], active from 2015 to 2018, were the initial decaying nodes that laid the theoretical groundwork for the study of macrophage functional heterogeneity. The emergence period of Ruffell B [2015] extends from 2016 to 2020, indicating that the research findings provide enhanced academic continuity and practical guidance in key areas, such as regulating lung cancer microenvironment homeostasis through macrophage polarization and understanding the mechanisms of tumor immune evasion. The surge periods for ten publications, Vitale I [2019], are focused between 2023 and 2025 (data cutoff date). These emerging trends indicate that the associated topics are gaining prominence as contemporary research themes.

Figure 7 Co-citation analysis and intellectual base identification. (A) Reference citation network. (B) Reference citation network clustering results. (C) The top 25 references with the strongest citation bursts.

Analysis of keywords

Table 6 displays the 20 most prevalent keywords in this domain. By combining the frequency of keyword occurrences with keyword clusters in the co-occurrence network, the principal research hotspots and themes in this domain can be discerned. Figure 8A depicts the co-occurrence clustering network of keywords. The results show that within the top 20 most prevalent keywords, the third cluster (blue) constitutes 50%, predominantly including terms such as macrophages (n=324), expression (n=192), tumor microenvironments (n=159), immunotherapy (n=126), M2 macrophages (n=120), and exosomes (n=58). This cluster investigates the regulatory network of macrophage polarization in tumor microenvironments, its therapeutic implications, and the molecular mechanisms underlying exosome-mediated intercellular signaling in macrophage phenotypic modulation. Secondly, the first cluster (red) constitutes 40%, with the primary keywords being controlled study (n=94), animal experiment (n=77), animal model (n=72), signal transduction (n=62), and Western blotting (n=59). The primary emphasis is on in vivo and in vitro experimental validation, as well as the investigation of molecular mechanisms related to the interaction between lung cancer and macrophage polarization.

Figure 8 Research frontiers and emerging trends in macrophage polarization and lung cancer. (A) Keyword co-occurrence clustering network diagram. (B) Keyword timeline chart. (C) Keyword Time Zone Map. (D) The top 25 keywords with the strongest citation bursts.

Figure 8B displays a timeline graph of the keywords and performs clustering on them while considering the temporal dimension. #0 lung cancer: this cluster encompasses the entire temporal axis, with the first node being comparatively substantial. This indicates that since 2010, lung cancer has persistently been a central focus of study in this domain, regularly garnering significant attention and establishing the foundation of the overall research framework. #1 dectin-1: This cluster appeared later than others, with its nodes primarily located in the middle and late stages of the study. This signifies that Dectin-1, a pattern recognition receptor predominantly found on myeloid cells, such as macrophages, has emerged as a focal point of investigation within the lung cancer immune milieu in recent years. #2 protein degradation: This cluster appeared later than others, with its nodes focused on the intermediate and late stages. This suggests that research on the protein degradation system, encompassing the ubiquitin-proteasome pathway and the autophagy-lysosomal pathway, has become a prominent area of investigation in lung cancer in recent years. #3 macrophage activation: This cluster spans the entire temporal axis, with highly populated nodes indicating that macrophage activation consistently plays a pivotal role in investigating the lung cancer tumor microenvironment and immune modulation. #4 acute lung injury: This cluster is relatively small with fewer nodes, suggesting that while it is linked to pulmonary pathological alterations, the research interest in lung cancer is quite restricted. It is primarily regarded as a consequence or concurrent condition. #5 macrophage polarization: The aggregation of nodes within this cluster transpires during the intermediate and later phases of the time axis, signifying that macrophage polarization has become a significant area of research in recent years, particularly in relation to the mechanisms of immune evasion and therapeutic response in lung cancer. #6 angiogenesis: While this cluster persists throughout the entire process, the nodes are unevenly scattered, suggesting that angiogenesis, as a crucial mechanism in tumor development, does not remain the focal point in lung cancer. #7 exosomes and #9 hyaluronic acid: These two clusters display significant nodes throughout particular timeframes, signifying that research about exosomes and hyaluronic acid has been a focal point in this domain during those intervals. #8 melanoma: This cluster is comparatively brief with a sparse node distribution, indicating that it primarily encompasses research trajectories intersecting with lung cancer (such as immunotherapy response or oncogenic signaling pathways), but has not evolved into a distinct and enduring area of emphasis.

Figure 8C presents the time-zone diagram of keywords in this research field. The results show that before and including 2016, keywords such as “macrophage polarization”, “lung cancer”, “expression”, “inflammation”, “breast cancer”, and “colorectal cancer” appeared frequently, indicating that early-stage research mainly focused on the expression regulation of macrophage polarization-related genes and proteins, and the fundamental mechanisms of tumorigenesis, development, and inflammatory response. Meanwhile, the concentrated occurrence of keywords including “m2 macrophages”, “differentiation”, “phenotype”, “monocytes”, and “angiogenesis” reflects that the research priority at this stage mainly centered on the differentiation and phenotypic characteristics of macrophage polarization phenotypes, and explored their functional roles in tumor proliferation, cell migration, apoptosis, angiogenesis, and inflammation-mediated processes. Notably, mechanism-related keywords such as “tumor microenvironments”, “immunotherapy”, “metabolism”, “metastasis”, and “immune response” emerged in 2015 and 2016, indicating that by the end of this stage, research had already expanded from pure phenotypic investigation to the preliminary exploration of mechanisms related to metabolic regulation, tumor metastasis and immune response, which laid a foundation for subsequent in-depth mechanism research. From 2017 to 2021, keywords such as “cytokines”, “epithelial mesenchymal transition”, and “cd4+ t lymphocyte” emerged with high frequency, indicating that based on the research on metabolism, metastasis and immune response conducted in 2015 and 2016, researchers further delved into the refined molecular mechanism levels including cytokine mediation, epithelial-mesenchymal transition and lymphocyte immune regulation, and improved the regulatory network of macrophages in the tumor microenvironment. Meanwhile, keywords such as “exosomes”, “micrornas” and “extracellular vesicles” appeared in a concentrated manner for the first time in this stage, which means that exosome-mediated intercellular communication has become a brand-new emerging research hotspot in this period, promoting the research on macrophage polarization mechanism to shift from basic mechanism analysis to molecular carrier-mediated refined regulation research, and greatly enriched the research dimension of this field. After 2022, keywords such as “tumor-associated macrophages”, “nanoparticles”, “targeted drug delivery”, “cancer therapy”, and “immune checkpoint inhibitors” frequently appeared, indicating that research hotspots have further extended toward clinical translation in areas including macrophage-targeted interventions, nanodelivery technologies, and precision immunotherapy. Meanwhile, disease-related terms like “lung adenocarcinoma”, “acute lung injury”, and “pulmonary diseases” increasingly emerged alongside sophisticated experimental techniques such as “genetic transfection” and “transwell assay”, making research settings more aligned with real-world clinical conditions and research methods more precise and diverse. This shift not only reflects a growing systematic and refined understanding of macrophage polarization regulatory networks but also demonstrates a comprehensive transition from basic mechanistic studies to clinical translation focused on precise therapeutic interventions.

Figure 8D displays the 25 terms exhibiting the most significant citation bursts in this domain. The results show that keywords like “expression”, “activation”, “cells”, and “macrophage polarization” became prominent in 2010, suggesting that research during this time concentrated on the expression of associated genes or proteins in macrophage polarization and their roles in lung cancer development and progression. From 2013 and 2015, pivotal terms including “differentiation”, “angiogenesis”, “alternative activation”, “progression”, “neutrophil”, and “tumor-associated leukocyte” emerged sequentially, signifying a deepening of research that began to explore the relationship between macrophage polarization and processes such as cell differentiation, angiogenesis, and alternative activation, alongside interactions with other immune cells like neutrophils and tumor-associated leukocytes. From 2015 to 2017, the prominence of key terms such as “tumor-associated leukocyte”, “invasion”, “metastasis”, and “lung cancer” increased markedly, indicating a substantial shift in research emphasis towards elucidating the impact of macrophage polarization on the invasion and metastasis of lung cancer cells. This study direction is crucial for clarifying the malignant course and prognosis of lung cancer. From 2017 to 2020, significant terms such as “suppressor cells”, “plasticity”, “growth”, and “cancer prognosis” emerged, reflecting a shift in research emphasis towards investigating the relationship between immunosuppressive cells and macrophage polarization, alongside the plasticity of macrophage polarization and its influence on tumor growth and cancer prognosis. From 2020 and 2022, terms such as “cancer prognosis”, “cytokine release”, “epithelial-mesenchymal transition”, “receptor”, “rna”, “in vivo study”, and “mechanisms” surfaced, signifying a shift in research towards cytokine release, epithelial-mesenchymal transition, receptor functionality, RNA regulation, in vivo experimentation, and the specific mechanisms associated with macrophage polarization, aimed at elucidating the molecular mechanisms and potential therapeutic targets of macrophage polarization in lung cancer.

Discussion

Overview of publications

The quantity of publications within a designated period indicates the research activity level and developmental path of the field (18). In the first phase [2010–2016], research on macrophage polarization in the field of lung cancer was still at the preliminary exploration stage. Studies mainly relied on traditional immunohistochemistry, flow cytometry, and in vitro co-culture systems, and focused on investigating the preliminary correlation between surface markers of M1 and M2 macrophages and the clinicopathological characteristics of lung cancer. Limited by technical constraints such as the lack of single-cell resolution and mature gene-edited animal models, the research output in this phase was limited, but it laid a conceptual foundation for subsequent studies. In the second phase [2017–2021], the annual number of publications in this field showed a steady growth trend. With the popularization and maturation of gene editing technology, researchers are able to systematically dissect the causal regulation of macrophage polarization by classical pathways, including IL‑4/signal transducer and activator of transcription 6 (STAT6), IFN‑γ/STAT1, nuclear factor kappa-B (NF‑κB), and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) (19). Meanwhile, the maturation of the tumor microenvironment concept in this phase has extended the scope of research from isolated macrophages to the network interaction among macrophages, tumor cells, fibroblasts, and T cells. Furthermore, at the technical and funding level, sustained investment in tumor immunology from institutions including the National Natural Science Foundation of China and NIH has promoted the stable output of high-quality research outcomes. The third phase [2022–2025] has commenced a period of significant advancement. This advancement during the period is presumably propelled synergistically by several critical elements. First, the maturation of single-cell sequencing, spatial transcriptomics, and in vivo imaging technologies around 2022 has enabled researchers to precisely dissect the heterogeneity and dynamic transition mechanisms of macrophage polarization in the lung cancer microenvironment, lowering technical barriers and deepening research depth (20). Second, the escalating prevalence of lung cancer and the growing issue of immunotherapy resistance have heightened interest in the field, as macrophage polarization directly influences tumor immune evasion and treatment responsiveness. Third, the engineered creation of innovative biological carriers has introduced new instruments for the exact modulation of macrophage phenotypes. Furthermore, the sustained attention from high-impact journals, including Nature Nanotechnology, Frontiers in Immunology, and Advanced Science, along with the strategic funding support from national key research and development programs, jointly constitute a critical external driving force for this field. With the in-depth integration of high-resolution omics technologies, biomaterial engineering, and clinical immunotherapy, research on lung cancer macrophage polarization is projected to maintain sustained rapid growth in the coming years and retain its position as a cutting-edge hotspot in tumor immunology.

Contributions of countries/regions

There are significant differences in the scientific research output and academic influence across different countries. Such discrepancies are not merely a simple quantitative comparison, but profoundly reflect the structural differences among countries in research paradigms, resource integration approaches, and innovation pathways in this field (21). China’s publication output in this field ranks among the highest globally. This phenomenon is not accidental, but is closely correlated with China’s systematic and sustained strategic investment in the field of tumor immunology in recent years. Through the establishment of high-level cancer research centers, large-scale clinical biobanks, and cutting-edge technological platforms, including single-cell sequencing and spatial transcriptomics, China has developed a complete research chain extending from clinical questions to fundamental mechanistic investigations, thereby achieving rapid knowledge accumulation in the research direction of macrophage polarization and lung cancer microenvironment regulation (22). Despite the large volume of publications, the overall academic impact of Chinese research outputs lags behind that of the United States and several European countries. The underlying reason for this discrepancy is that a large proportion of early Chinese studies focused predominantly on descriptive associations between macrophage polarization phenotypes and the clinicopathological characteristics of lung cancer, with limited original exploration of in-depth mechanisms such as core signaling pathways, metabolic reprogramming, and epigenetic regulation. Although such phenotype-driven research is necessary and foundational in the initial stage of knowledge accumulation, it is difficult to generate sustained and high-level attention and citations in the international academic community due to its limited depth of innovation. Furthermore, some research findings are published in domestic or regional journals, and constrained by language and open access barriers, they have not been fully integrated into the mainstream international academic communication network, which further reduces the breadth and depth of their knowledge diffusion.

Although European and North American countries do not have an advantage in publication volume in this field, their research outputs generally feature high conceptual originality and technological leadership. Such an advantage is rooted in the long-term accumulation of the United States in interdisciplinary integration, a high-impact journal ecosystem, and the complete basic-translational research chain. A representative example is the landmark paper “Iron oxide nanoparticles inhibit tumour growth by inducing pro-inflammatory macrophage polarization in tumour tissues”, published by American scholar Steven Zanganeh in Nature Nanotechnology (23). This study first verified in a murine lung cancer model that iron oxide nanoparticles (NPs) can reprogram macrophages to polarize from the pro-tumor M2 phenotype to the anti-tumor M1 phenotype, thereby remodeling the immune microenvironment and significantly inhibiting tumor progression. Such mechanism-driven and intervention-oriented research not only expands the theoretical boundary of macrophage polarization regulation but also directly provides translatable new targets and strategies for lung cancer immunotherapy. In summary, the aforementioned discrepancy between China and countries/regions, including Europe and North America, fundamentally reflects distinct developmental models for the advancement of scientific research. Through a systematic research layout, China has achieved scale advantages and rapid knowledge accumulation in this field, while Europe and North America drive breakthroughs in in-depth mechanisms and clinical translation through conceptual originality and technological leadership. The two models do not differ in terms of superiority or inferiority; instead, they form a complementary landscape of large-scale validation and source innovation. Furthermore, China’s central position in the global cooperation network of this field is not only a key hub for knowledge flow, but also enables it to combine its own scale advantages with the original innovation advantages of Europe and the United States through in-depth cooperation such as the joint establishment of cooperative laboratories, sharing of humanized animal models, and collaboration of multi-center clinical cohorts, thereby substantially accelerating the clinical translation process of macrophage polarization targeting strategies from the laboratory to clinical application.

Contributions of institutions

In terms of institutional contributions, Fudan University, Chinese Academy of Medical Sciences, Shanghai Jiao Tong University, and Zhejiang University have become representative research forces in this field by virtue of their differentiated advantages in scientific research resources. The fundamental reason why Fudan University has developed prominent research advantages lies in its deep integration of the large-scale lung cancer clinical sample repository and complete follow-up data system accumulated over a long period of time by its affiliated Cancer Hospital and Zhongshan Hospital, which provides an irreplaceable fundamental platform for the systematic analysis of the dynamic evolution law of macrophage polarization in the tumor microenvironment. Leveraging this endowment of clinical resources, multiple research teams from the university have conducted continuous and in-depth exploration of the regulatory mechanism of macrophage polarization. For example, the research team led by Dr. Fu systematically clarified the molecular pathway through which the IL‑4/STAT6 signaling axis drives M2 polarization to promote immune evasion in lung cancer, revealed the synergistic regulatory network of cytokines such as TGF‑β and colony-stimulating factor-1 (CSF1) in the tumor microenvironment, and developed novel targeted immunomodulatory strategies targeting macrophages based on these findings (24). Meanwhile, through the integration of interdisciplinary experimental platforms including basic medicine, immunology, and clinical oncology, Fudan University has enabled the routine application of cutting-edge technologies such as single-cell sequencing and spatial transcriptomics, thereby establishing systematic academic advantages in the analysis of macrophage heterogeneity, the depiction of functional differentiation trajectories, and research on the association between the above characteristics and clinical translation (25). The Chinese Academy of Medical Sciences, leveraging the National Center for Respiratory Medicine and key laboratories, has focused on the dynamic regulatory network of immune cells in the tumor microenvironment. By integrating sequencing data of circulating tumor DNA with research on tumor-infiltrating immune cells, it has deeply elucidated the mechanisms by which epidermal growth factor receptor (EGFR) mutations lead to resistance to targeted therapy, achieving significant results (26). Shanghai Jiao Tong University, leveraging the deep expertise of its affiliated Chest Hospital and Ruijin Hospital in precision diagnosis, treatment, and translational research for thoracic tumors, has extended its research focus to the interactive regulatory network among immune cells such as macrophages, T cells, and dendritic cells, systematically investigating how macrophage polarization status influences the development of lung cancer drug resistance and long-term patient outcomes (27,28). The research strengths of Zhejiang University are embodied in the innovative integration of artificial intelligence technology with basic and clinical research on lung cancer. In particular, digital quantitative analysis methods have been introduced into macrophage-related research. Through the constructed deep learning algorithm, this institution can automatically identify and accurately quantify the density, spatial distribution characteristics, and polarization phenotype of tumor-associated macrophages (TAMs) from the whole-slide digital pathology images of lung cancer tissue sections, and further construct an association prediction model for patient prognosis and outcome (29). This methodological breakthrough not only overcomes the subjectivity and semi-quantitative limitations of traditional pathological assessment but also provides a new technical pathway for large-scale, standardized analysis of macrophage polarization in the functional context of heterogeneous lung cancer microenvironments. In conclusion, the four aforementioned institutions, through distinct research paradigms including clinical resource-driven approaches, basic frontier-leading, immune network orientation, and technological innovation-driven strategies, have collectively promoted the transformation of China’s research on macrophage polarization and lung cancer from large-scale data accumulation to in-depth mechanism exploration and interdisciplinary development.

Contributions of authors

In terms of author contributions, Wang YiChing and Yang Bo, as representative researchers in this field, the differences between their academic trajectories and impact characteristics profoundly reveal the disciplinary development logic of the evolution of the lung cancer and macrophage polarization research field from mechanism elucidation to translational promotion. Wang Yi-Ching, as the principal investigator in the Department of Pharmacology at National Cheng Kung University, has long focused on the mechanistic role of macrophage polarization in the lung tumor microenvironment. She has led multiple key research projects on tumor immune regulation funded by Taiwan’s Ministry of Science and Technology and Ministry of Health and Welfare. Collaborating with scholars such as Tzeng Hong-Tai, Hui Hua Chang, and Yang You-En, she has published numerous papers on macrophage polarization and lung cancer, investigating mechanisms such as the Rab37-IL-33/ST2L positive feedback loop driving M2 macrophage expansion and the DNMT1-p53 axis mediating estrogen-promoted M2 polarization. She has also advanced translational research on combining IL-33 or ST2L blockade with conventional therapies to reverse immunosuppressive microenvironments, significantly promoting the clinical application of macrophage polarization in immune regulation and prognosis assessment for lung cancer (30-32). This research paradigm, which starts from specific molecular targets and ultimately returns to preclinical intervention validation, endows her research outcomes with high integration and translatable operational value, thereby playing a critical leading role in promoting the clinical translation of macrophage polarization theory to immunoregulation and prognostic evaluation of lung cancer. Nevertheless, such systematic research involving multi-node, multi-pathway, and multi-level regulatory networks often requires long-term academic accumulation and multi-dimensional validation to fully realize its impact. In addition, since some of her research findings have been published in regional academic journals, the breadth of academic dissemination and the intensity of immediate citation remain relatively moderate. Yang Bo from Zhejiang University also conducts in-depth research on lung cancer and macrophage polarization. He has conducted two core mechanistic studies to deeply explore how the hypoxia-ERK signaling axis selectively drives M2 polarization of macrophages and enhances metastasis in non-small cell lung cancer, and how gefitinib inhibits M2 macrophage polarization via the STAT6 pathway in Lewis lung cancer (33). These two mechanistic studies directly target two critical challenges in clinical lung cancer treatment: drug resistance induced by the hypoxic tumor microenvironment and the immunoregulatory effect of targeted drugs on immune cells. The studies clearly define the bidirectional regulatory role of physical microenvironmental factors and pharmaceutical intervention on macrophage polarization at the mechanistic level, and both the STAT6 and ERK signaling nodes have clear potential for pharmaceutical intervention. This research paradigm, which is oriented toward addressing unmet clinical needs and takes a single key signaling axis as a breakthrough, has enabled his findings to gain extensive attention and citations from international peers rapidly after publication, reflecting the current field's preference for research outcomes with high therapeutic relevance and strong mechanistic insight.

Notably, the author collaboration network exhibits a typical fragmented pattern characterized by strong intra-cluster connections and weak inter-cluster interactions. This structural discontinuity is not a random phenomenon, but an inevitable outcome of the fact that the research field of macrophage polarization and lung cancer is still in a stage of rapid expansion without mature integration. Different research teams usually conduct independent studies centered on their specialized signaling pathways or technical platforms, and multi-centered systematic collaboration mechanisms across pathways, systems, and regions have not yet been established. From the perspective of temporal dynamics, the representative work by Yang Bo emerged at an earlier stage, which provided an important theoretical framework and methodological reference for subsequent research. In recent years, a large number of emerging researchers have entered this field, presenting the characteristics of rapid knowledge diffusion and diversified research directions. This pattern profoundly indicates that to achieve the leap from isolated breakthroughs to network-based advancement in the field of macrophage polarization regulation in the future, it is necessary to proactively break the silo effect among existing author clusters through government policy guidance, targeted research funding support and continuous improvement of team collaboration mechanisms, and promote substantive cooperation among different teams in interdisciplinary directions including metabolic reprogramming, epigenetic regulation, nano-immunology engineering and artificial intelligence-assisted analysis.

Contributions of journals

In terms of journal contributions, the distribution of research results and knowledge flow path in this field revealed the disciplinary characteristics of the evolution of lung cancer and macrophage polarization research from molecular phenotype description to immune network regulation. Frontiers in Immunology, a prominent open-access journal in international immunology, publishes the highest volume of research in this domain, largely due to its emphasis on fundamental regulatory mechanisms, including cytokine signaling, immune checkpoints, and microenvironmental interactions (34). This closely aligns with the ongoing paradigm shift in the field—from inquiring “how macrophages polarize into M1 or M2” to exploring “how polarization states are coordinately regulated by various immune signals within the lung cancer microenvironment and how this affects therapeutic responses. Meanwhile, the high citation frequency of relevant publications in Nature Nanotechnology indicates that research on macrophage polarization has transitioned from passive observation to active intervention, exemplified by the groundbreaking study on reprogramming M2 polarization toward the M1 phenotype using iron oxide NPs (23). Although such findings are currently at the preclinical stage, verified via in vitro cell experiments and in vivo animal model validation, they have demonstrated that the polarization state of macrophages is not irreversible, but can be precisely regulated by exogenous nanomaterials, which provides a novel instrumental strategy for overcoming the immunosuppressive microenvironment of lung cancer. Furthermore, in the knowledge diffusion trajectory of this field, the knowledge transfer from “molecular biology and genetics” to “molecular biology and immunology” clearly outlines the profound paradigm shift in this field. Early research primarily relied on molecular biology approaches to identify expression changes of polarization-associated genes, and most research findings were published in specialized molecular biology journals such as Molecular Cancer and Molecular Cell. With the deepening of understanding, researchers have recognized that macrophage polarization is a dynamic network process co-regulated by multiple immune cells, cytokines, and metabolites in the tumor microenvironment, and the mere description of molecular events is insufficient to explain the functional heterogeneity of macrophage polarization in lung cancer progression. Therefore, these molecular-level findings must be reinterpreted within the holistic framework of immunology. For instance, the phosphorylation of STAT6 is not merely a biochemical event regulated by IL-4/IL-13, but also a hub mechanism that drives M2 macrophage polarization and promotes immune evasion of lung cancer and disease progression (35). This cognitive transition from molecular mechanisms to immune functions has led to an increasing number of research findings in this field being accepted and disseminated by high-impact journals in immunology and oncology, and also suggests that future research should break through the boundaries of single disciplines, proactively integrate the molecular regulatory mechanisms of macrophage polarization into the complex network of the tumor immune microenvironment, and improve the systematicity and translational value of research through multidisciplinary collaborations such as nanotechnology, metabolomics and single-cell analysis, to promote the advancement of this field towards more mature theoretical integration and clinical translation.

Contributions of references

In terms of reference contributions, the current knowledge base of research on lung cancer and macrophage polarization is predominantly shaped by macro-level epidemiological data and systematic review literature. The paper with the highest average annual citation frequency is “Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries” (36). Although this type of macro-level cancer statistical report is not an original experimental study focusing on macrophage polarization, it has consistently remained a core component of highly cited literature in this field. This phenomenon does not stem from the complexity of its methodology, but rather from the irreplaceable disease background it provides for all explorations of micro-level mechanisms. Without a clear positioning of this macroscopic disease landscape, any discoveries related to cytokines, signaling pathways, or nanomaterials will lose their directionality and urgency for clinical translation. Therefore, the continuous citation of such macro-level epidemiological literature essentially reflects the collective consensus of researchers in this field on the clinical relevance of research questions: every mechanistic study must ultimately address the unmet clinical needs in the diagnosis and treatment of lung cancer. Systematic review articles also occupy a central position in the foundation of knowledge, with their deeper significance lying in systematically integrating scattered and even seemingly contradictory experimental findings into a coherent theoretical framework. These reviews are not merely compilations of existing knowledge; rather, they were the first to incorporate multiple parallel signaling pathways—including IFN-γ/STAT1, IL-6/STAT3, CSF-1/CSF-1R, TLR/NF-κB, and miRNA-130a/PPAR-γ—into a unified analytical model (37,38). They clearly identified the polarization shift from M1 to M2 as a critical decision point in lung cancer immune evasion, and systematically explained how external driving forces such as tumor microenvironmental hypoxia, lactate accumulation, and tumor-derived cytokines reshape macrophage polarization profiles. Furthermore, they delineated the multi-pathway network through which M2-type TAMs promote lung cancer progression by establishing immunosuppressive niches, inducing angiogenesis, and triggering epithelial-mesenchymal transition. In essence, these reviews transform fragmented molecular data into testable mechanistic hypotheses and actionable therapeutic targets, thereby providing researchers with a shared theoretical and reference framework that helps prevent redundancy and fragmentation within the field.

Based on the thematic correlations and temporal distributions revealed by cluster analysis, the evolution of research topics in this field presents a clear progressive trajectory from phenotypic identification to mechanistic elucidation, and then to translational application. Early work mainly focused on the identification and classification of TAM phenotypes (#6 TAMs), aiming to address the fundamental question of what macrophage subtypes exist in the lung cancer microenvironment. After the phenotypic heterogeneity was sufficiently validated, the research focus naturally shifted to the functional regulatory mechanism of polarization, among which the role of signaling pathways (#2 NF-kappa B) has become a core topic, as it directly connects inflammatory signals, metabolic factors in the microenvironment, and cellular functional status. With the gradual accumulation of mechanistic research, the demand for clinical translation has become increasingly prominent. In particular, the drug resistance problem encountered in lung cancer immunotherapy has continuously driven basic research to identify novel targets for combined intervention. Against this background, natural intercellular communication carriers represented by exosomes (#0 exosomes) have received extensive attention, and researchers have attempted to utilize or intervene in endogenous signal transduction to regulate the polarization direction; while the application of artificial NPs (#1 iron nanoparticles) marks the expansion of research strategies from phenotypic observation and mechanistic analysis to active intervention, that is, directly altering the polarization state of macrophages through engineering approaches. It should be emphasized that high-impact research findings have been continuously generated in fields including signaling pathways, epigenetic regulation, and macrophage phenotypes to date. The fundamental cause for this sustained output lies in the fact that clinical drug resistance has not yet been fundamentally resolved, and researchers still need to identify potential targets for reversing drug resistance from these fundamental regulatory networks. In conclusion, the evolution of research topics in this field reflects the progressive advancement of scientific questions, the cross-fertilization of research methodologies, and the extension of research objectives from mechanistic understanding to intervention strategies, which fully demonstrates the two-way driving relationship between basic research and clinical needs.

Research trends

This research, based on keyword and reference analysis, reveals the evolving research focuses in this field over time. Beginning with initial representative keywords, including “expression”, “macrophage polarization”, “lung cancer”, “inflammation”, “M2 macrophages”, “angiogenesis”, and “differentiation”, and progressing to subsequent keywords such as “tumor microenvironment”, “metabolism”, “metastasis”, “exosomes”, “nanoparticles”, and “immune checkpoint inhibitor”. These trends mostly encompass: (I) advancing beyond the characterization of molecular phenotypes to the comprehensive regulation mechanisms of the microenvironment: initial research primarily concentrated on delineating surface markers associated with macrophage polarization (e.g., CD86, CD206) and their fundamental functional phenotypes (e.g., pro-inflammatory or anti-inflammatory effects), along with the preliminary correlations of these phenotypes to the onset and progression of lung cancer (39,40). Research has increasingly focused on the interactions between macrophages and various cellular components in the tumor microenvironment, including tumor cells, T cells, and fibroblasts. It also investigates the regulatory mechanisms governing macrophage polarization, influenced by cytokines, chemokines, and physical factors within the microenvironment (41,42). (II) Integration of singular signaling pathways into multidimensional regulatory mechanisms: preliminary investigations mostly concentrated on the functions of classical signaling pathways, including IL-4/STAT6 and IFN-γ/STAT1, in the macrophage polarization process (43). In recent years, researchers have increasingly combined metabolic reprogramming, including the equilibrium between glycolysis and oxidative phosphorylation (OXPHOS), with cytokine signaling networks to elucidate the intricacies of polarization regulation from a systematic perspective (44). (III) Transition from fundamental mechanism research to targeted intervention and translational application: the widespread utilization of innovative biological carriers, including exosomes and NPs, alongside engineering tools, has led to a gradual shift in research emphasis from investigating the fundamental polarization mechanisms of macrophages to the precise modulation of their polarization through these instruments. Simultaneously, the advent of the term “immune checkpoint inhibitor” has facilitated more precise intervention tactics and treatment concepts for clinical application. For instance, blocking CSF-1R to counteract the immunosuppressive milieu can markedly improve the efficacy of programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors (45).

Against the aforementioned background, to achieve the transition from qualitative description to cross-study data comparability, the standardization of biomarkers for macrophage polarization identification remains an urgent unmet need. Currently, there exist significant discrepancies in the biomarkers applied to distinguish M1 and M2 polarization across different studies, rendering research results difficult to compare directly. For instance, some studies rely on iNOS/NO while others adopt CD86/MHCII to identify M1 polarization; for M2 polarization, some studies take CD206 as the sole identification marker, while others prioritize CD163 or IL-10/Arg-1 (46-49). To complicate matters further, there are inherent differences in the biomarker profiles between human- and murine-derived macrophages (e.g., FIZZ1 and Ym1/2, commonly used for identifying murine M2 polarization, are not expressed in human macrophages) (50). In addition, many studies determine the polarization direction solely based on a single biomarker, ignoring the intrinsic feature that macrophage polarization is essentially a continuous spectrum process. This heterogeneity restricts knowledge integration across different studies and poses a major challenge to the standardized development of this field. Based on the above analysis, we propose the following standardized pathways for future research: First, establish a core biomarker panel: M1 polarization should at least include iNOS/NOS2 and CD80/CD86, and M2 polarization should at least include CD206 and CD163; second, report results stratified by species (human/mouse) and detection methods (flow cytometry/immunohistochemistry), with clear specification of antibody clone numbers and threshold settings; third, adopt a multi-marker scoring system or flow cytometry co-expression analysis to capture the phenotypic profile characteristics of macrophages. The proposed pathways are expected to improve the comparability of cross-study data, lay a methodological foundation for subsequent systematic integration and meta-analysis, and promote the evolution of this field from fragmented evidence to a standardized knowledge system.

Research hotspots

Hotspot analysis is helpful in identifying the cutting-edge developments and evolving trends in specific fields (51). Keywords, as the concise expression of the core content of a document, can precisely map the research topic and academic focus. This study, based on the analysis of keyword co-occurrence, clustering, and emergent results, systematically explored the phased evolution characteristics of macrophage polarization in lung cancer research. In the first stage [2010–2016], research primarily focused on the phenotypic description of macrophage polarization and its preliminary association with the pathological features of lung cancer. High-frequency keywords such as macrophage polarization, m2 macrophages, angiogenesis, differentiation, lung cancer, expression, and inflammation reflected the exploration of the phenotypic characteristics of macrophage polarization, tumor proliferation, and inflammatory responses. In the second stage [2017–2021], the emergence of keywords such as cytokines, epithelial-mesenchymal transition, metabolism, exosomes, and microRNAs marked the gradual shift of research from phenotypic observation to research hotspots such as signaling pathways, metabolic reprogramming, and exosome-mediated intercellular communication. In the third stage [2022–2025], the frequent appearance of keywords such as NPs, immune checkpoint inhibitors, targeted drug delivery, TAM, and dectin-1 indicated that the research hotspots had further expanded to nanodelivery systems, targeted intervention of macrophages, and the response mechanism of immunotherapy. The research paradigm has accelerated the extension from basic mechanism analysis to precision treatment and clinical translation. The above three-stage evolution path clearly reveals the knowledge leap in this field from phenomenon description to mechanism integration and then to intervention transformation, laying a solid bibliometric foundation for further in-depth exploration of specific regulatory mechanisms and treatment strategies.

Preliminary association between the description of macrophage polarization phenotypes and the pathological features of lung cancer [2010–2016]

Research on macrophage polarization during this stage predominantly adheres to the classic M1/M2 dichotomous classification system. In in vitro models, unstimulated resting macrophages (M0), upon stimulation by different microenvironmental signals, can undergo directed differentiation into classically activated (M1) and alternatively activated (M2) macrophages with opposed functions (52). Among them, M1 macrophages are mainly induced by LPS, IFN-γ, or granulocyte-macrophage colony-stimulating factor (GM-CSF). Their polarization process involves the coordinated activation of signaling pathways such as TLR4/NF-κB and JAK-STAT1. These cells highly express CD80, CD86, MHC class II molecules, and TLR2/4 on their cell surfaces. Simultaneously, they secrete pro-inflammatory factors such as TNF-α, IL-1β, IL-6, IL-12, and inducible nitric oxide synthase (iNOS), mediating Th1-type immune responses and demonstrating anti-tumor potential in experimental models (7). In contrast, M2 macrophages are induced by stimuli such as IL-4, IL-13, IL-10, TGF-β, or immune complexes. Their polarization process is mainly mediated by the JAK-STAT6 signaling pathway. These cells highly express markers such as CD206, CD163, and IL-1RII on their cell surfaces. They also secrete anti-inflammatory factors such as IL-10 and TGF-β, as well as Th2-type chemokines such as CCL17, CCL18, and CCL22, participating in tissue repair, angiogenesis, and immune suppression (53).

Based on the aforementioned phenotypic framework, researchers in this stage preliminarily explored the association between the polarization state of macrophages and the clinicopathological features of lung cancer. Multiple retrospective studies and animal experiments have shown that the infiltration density of M1 macrophages in lung cancer tissues is positively correlated with the prognosis of patients: M1 macrophages drive the Th1 immune response by secreting IL-12, promote the recruitment and activation of CD8⁺ cytotoxic T cells, and simultaneously release effector molecules such as TNF-α to directly inhibit the proliferation and metastasis of tumor cells (54,55). However, most of these evidences are derived from in vitro induction or xenograft tumor models, and the true association in humans requires further validation through clinical studies with larger sample sizes. In contrast, M2 macrophages are significantly associated with the progression, lymph node metastasis, and poor survival rate of lung cancer. M2 macrophages create an immunosuppressive microenvironment by secreting immunosuppressive cytokines such as IL-10 and TGF-β, thereby inhibiting the function of effector T cells; at the same time, they release pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) to promote the formation of new tumor blood vessels (56). In addition, M2 macrophages can also activate the Smad signaling pathway by secreting TGF-β, and cooperate with the extracellular matrix degradation mediated by matrix metalloproteinases (MMPs) to jointly accelerate the epithelial-mesenchymal transition (EMT) process. Multiple retrospective clinicopathological studies have further revealed that lung cancer patients with high expression of M2 markers CD163 or CD206 often present with a higher tumor node metastasis classification (TNM) stage and a shorter overall survival (57-59). However, most studies during this period were cross-sectional observations or small-sample cohort studies, lacking longitudinal tracking of the dynamic changes in macrophage polarization. Moreover, most studies made judgments based solely on tissue samples at a single time point, making it difficult to comprehensively reflect the spatiotemporal heterogeneity of the polarization state in the tumor microenvironment. These methodological limitations suggest that subsequent studies should utilize single-cell spatiotemporal omics technology and a prospective cohort design to dynamically analyze the evolutionary trajectory of macrophage polarization, thereby providing a more reliable basis for the formulation of precise immunotherapy strategies.

Research on the mechanisms of macrophage polarization mediated by signaling pathways, metabolic reprogramming, and exosomes [2017–2021]

From 2017 to 2021, researchers’ understanding of the regulatory mechanism of macrophage polarization evolved from a description of a single signaling pathway to an analysis of an interactive network of multiple pathways. During this period, the IL-4/STAT6 axis was repeatedly confirmed as the core pathway driving the acquisition of M2-like functions. Fu et al. confirmed, based on a lung cancer mouse model, that the continuous activation of this pathway can significantly expand the population of myeloid-derived suppressor cells, thereby accelerating malignant progression (24). Meanwhile, Tariq et al. found that the EGFR-targeted drug gefitinib can block the establishment of the M2-like state by inhibiting STAT6 phosphorylation, for the first time directly associating clinical anti-tumor drugs with macrophage phenotype regulation (33). Notably, some studies have begun to explore the antagonistic relationship between different signaling axes. For example, the research team led by Korbecki et al. showed that the accumulated lactic acid or low oxygen tension in the tumor microenvironment can stabilize HIF-1α, which in turn interferes with the nuclear translocation efficiency of the NF-κB signaling axis, thereby inhibiting the transcription of M1-type related pro-inflammatory factors (60). This mechanism not only explains the phenomenon of generally low expression of M1-like effector molecules inside solid tumors but also reveals the cross-regulation between the transcription program and the classical inflammatory signaling pathway. The breakthrough in this stage lies in the realization that the linear model in which a single pathway determines a single phenotype is insufficient to describe the complex in vivo reality, and instead, the view that multiple signal inputs are jointly integrated to determine the polarization direction is accepted. However, at that time, most of the evidence was derived from in vitro-induced bone-marrow-derived macrophages or xenograft tumor models. High-throughput single-cell dynamic detection methods, such as imaging mass cytometry and multi-parameter flow cytometry combined with phosphorylated antibodies, are still generally lacking for the simultaneous in situ quantification of the activities of multiple signaling pathways within the same macrophage population. As a result, it is difficult to accurately characterize the real weight relationships and dynamic switching rules among pathways.

Alongside the networked understanding of signal pathways, metabolic reprogramming has been confirmed not only as a phenomenon accompanying polarization but also as an active force driving phenotypic transformation. After 2018, multiple studies based on the co-culture system of lung cancer have shown that macrophages polarizing towards the M1-like phenotype exhibit a significant enhancement of aerobic glycolysis, characterized by a sharp increase in glucose uptake rate, upregulation of lactate dehydrogenase activity, and inhibition of mitochondrial oxidative phosphorylation function (61,62). In contrast, cells polarizing towards the M2-like phenotype show a dependence on the fatty acid oxidation pathway, with significantly elevated expression levels of key lipid metabolism genes such as carnitine palmitoyltransferase 1A (CPT1A) and CD36 (63). This dichotomy between M1 glycolysis and M2 fatty acid oxidation is relatively clear in the in vitro bone-marrow-derived macrophage induction model. However, in the complex lung cancer microenvironment, TAMs are more likely to present a mixed or transitional metabolic profile. Lukyanova et al. found that the metabolic intermediate succinate can stabilize HIF-1α by inhibiting prolyl hydroxylase, forming a positive feedback loop (64). This finding indicates that such metabolic regulatory patterns may be widely present in different polarization subtypes and do not strictly follow the above-mentioned dichotomy, suggesting that the regulation of polarization by metabolites has universality across classic phenotypic classifications. The revelation of metabolic reprogramming provides a new entry point for intervening in macrophage polarization. Compared with targeting upstream signal kinases, regulating the activity of metabolic enzymes or the concentration of metabolites offers an intervention approach different from classic signal pathway inhibitors. However, the selective advantage of this metabolic intervention strategy over kinase inhibitors still needs to be rigorously verified through cell-type-specific delivery strategies such as nanocarriers or genetic manipulation. In addition, the two-dimensional culture system is commonly used in the research at this stage, overlooking the systematic remodeling effect of a large amount of metabolic waste, such as lactate, ketone bodies, and glutamine, released by tumor cells and fibroblasts in the lung cancer microenvironment on the metabolic profile of macrophages. This difference in the metabolic environment between in vitro and in vivo settings may be an important reason why the effectiveness of some metabolic intervention strategies in animal experiments falls short of expectations.

In addition to intracellular signaling and metabolic regulation, exosomes, as nanoscale carriers for intercellular communication, have rapidly evolved from peripheral tools to core frontiers during this period. The vast majority of studies indicate that exosomes derived from lung cancer cells tend to induce macrophages to acquire an immunosuppressive M2-like phenotype. For instance, multiple studies have confirmed that small RNAs such as miR-21 and miR-222 carried by exosomes can activate the PI3K/Akt pathway by targeting PTEN, thereby promoting M2 polarization (65-67). Contrary to this mainstream view, Tzeng et al. first revealed that exosomes derived from lung cancer cells release soluble ST2 protein through Rab37-mediated exocytosis, thus guiding macrophages towards an M1-like phenotype (30). This discovery challenges the single perception that tumor exosomes only promote M2 polarization and reveals the functional heterogeneity of tumor-derived exosomes. The core contribution of exosome research at this stage lies in demonstrating that the polarization state of macrophages is not solely determined by the cell’s autonomous program, but rather is the result of intercellular communication actively regulated by tumor cells. This shift in perspective lays a theoretical foundation for the subsequent development of engineered exosomes as drug delivery systems to achieve targeted reprogramming of macrophage phenotypes. In summary, from 2017 to 2021, the interaction network of signaling pathways, the active drive of metabolic reprogramming, and exosome-mediated inter-cellular regulation have collectively propelled macrophage polarization research from the descriptive stage to a new height of mechanism integration and exploration of intervention strategies.

Translational research on the regulation of macrophage polarization by NP targeted delivery and immune checkpoint inhibitors [2022–2025]

Between 2022 and 2025, researchers have shown a trend of presenting more engineering intervention methods with clinical translation potential. During this period, NPs have evolved from passive drug carriers to active immune regulation tools. In terms of inducing the reversal of TAMs from the M2 to the M1 phenotype, based on their previous work, Horvat et al. further verified the translational potential of superparamagnetic iron oxide NP complexes containing cross-linked polymer micelles (SPION-CCPMs) in the lung cancer microenvironment. After intratracheal instillation, SPION-CCPMs not only stimulate TAMs to secrete key molecules with tumor-killing activity (nitric oxide, TNF-α), but also significantly reshape the immunosuppressive microenvironment of Eml4-ALk lung tumors, manifested as the specific recruitment of CD8⁺ T cells, and delay the regrowth of drug-resistant tumors after first-line treatment with tyrosine kinase inhibitors (68). In addition, Li et al. constructed an ultrasound-responsive nanocarrier (FA-PFNB-SIRPα siRNA) to co-deliver Fe₃O₄ NPs and SIRPα siRNA. In in vivo tumor models, it effectively knocked down SIRPα, inhibited M2-type polarization, and promoted TAMs to phagocytose tumor cells, providing a new strategy for macrophage-based immunotherapy (69).

The aforementioned NPs strategy not only achieves precise regulation of macrophage polarization but also provides a novel delivery vehicle for combined immune checkpoint inhibition (ICI) therapy. For example, Su et al. utilized microfluidic technology to construct pH-hypersensitive polymeric nanovesicles (NCPA), which can precisely deliver anti-CD47 and anti-PD-L1 antibodies to the lung cancer microenvironment. In the mouse Lewis lung cancer model, NCPA significantly enhances intratumoral antibody accumulation, promotes the reshaping of TAMs towards an anti-tumor phenotype, and increases the infiltration of dendritic cells and CD8⁺ T cells, providing an efficient nano-delivery platform for lung cancer immunotherapy targeting the CD47-SIRPα axis (70). In addition to nanocarriers, non-nanodrug research has further revealed the regulatory role of macrophages in the response to PD-1/PD-L1 blockade therapy. At the level of drug resistance mechanisms, Laight et al. found through animal model studies that Fes-deficient macrophages can promote the activation and initiation of CD8⁺ T cells by enhancing antigen presentation and the production of pro-inflammatory cytokines, making tumors more sensitive to anti-PD-1 therapy. This discovery provides a new macrophage-targeted strategy for improving the efficacy of immune checkpoint blockade (71). In addition, anagliptin, a DPP4 inhibitor commercially available for the treatment of type 2 diabetes in clinical practice, has also been proven to enhance the efficacy of PD-L1 blockade by inhibiting macrophage differentiation and M2 polarization, providing ideas for drug repositioning to overcome the treatment challenges in drug-resistant patients (72).

In the area of novel immunotherapy targets, Dectin-1 has attracted increasing attention due to its potential functions in macrophage immune regulation. As a C-type lectin receptor, Dectin-1 has traditionally been considered to be involved in the antifungal immune response. However, recent studies have revealed that it is also expressed on the surface of TAMs in the tumor microenvironment and can recognize abnormally glycosylated ligands derived from tumors. For instance, Wang et al. discovered through the integration of bioinformatics analysis and validation of clinicopathological samples that the C-type lectin domain containing 7A (CLEC7A) gene, which encodes Dectin-1, is significantly up-regulated in gliomas. Its high expression is closely associated with the increased infiltration of M2-type macrophages and the formation of an immunosuppressive microenvironment. Further functional studies have shown that the knockout of CLEC7A can significantly inhibit the chemotaxis and polarization of M2-type macrophages, thereby reshaping the immune microenvironment and improving the prognosis of patients (73). These findings suggest that Dectin-1 is an important potential target for regulating M2 polarization of macrophages and reprogramming pathological macrophages. However, the specific regulatory mechanisms of Dectin-1 in the microenvironments of other tumors, such as lung cancer, still need to be thoroughly analyzed.

In summary, the research conducted between 2022 and 2025 has transcended the previous paradigm centered on mechanism description, propelling the regulation of macrophage polarization from basic mechanism research to a substantial leap towards dynamic reprogramming and engineered intervention. However, there are still common bottlenecks in this stage. Currently, most of the combined strategies of NPs and immune checkpoint inhibitors are in the pre-clinical verification stage, and their long-term safety and tumor specificity still need to be fully verified; there is a lack of standardization for dynamic monitoring indicators of macrophage polarization states; the heterogeneity degree of M2-type TAMs in the tumor microenvironment of different patients has not been incorporated into the consideration of treatment stratification. All these pose higher requirements for precision medicine in future clinical trial design.

Strengths and limitations

This bibliometric analysis provides a comprehensive overview for researchers in lung cancer and macrophage polarization; however, numerous limitations persist. Firstly, using the WoSCC and Scopus databases in this study may exclude pertinent research not indexed by these databases, thereby undermining the comprehensiveness of the data. The justification for choosing the WoSCC in this study is its global acknowledgment as a reputable academic resource platform. Their superior publications are especially appropriate for bibliometric examination (74). Scopus, the preeminent abstract and citation database of peer-reviewed literature, has achieved extensive global acclaim. It is characterized by a more comprehensive collection of documents, providing significant supplementary transdisciplinary academic resources for bibliometric analysis (75). Secondly, establishing the cut-off date for literature retrieval in this study as August 1, 2025, may result in the omission of works that are still in the publication process. Incorporating data from 2025 can accurately reflect current research trends and developmental trajectories in this sector, thereby considerably improving the timeliness of the analytical outcomes. Finally, the sole inclusion of literature published in English may lead to inadequate sample representativeness, thereby limiting the thorough representation of the global research landscape. The reason is that English, as the principal language of international academic communication, serves as the primary medium for publishing significant research outcomes in this domain. Its scholarly norms and global reach receive extensive recognition.

In addition, this study primarily conducts a bibliometric analysis based on published academic papers and does not systematically incorporate clinical trial registration information data from sources such as ClinicalTrials.gov and the Chinese Clinical Trial Registry (ChiCTR) in this field. Clinical trial registration information reflects the research design, intervention measures, and primary outcome indicators in the translation from basic research to clinical practice. It serves as an important data source connecting laboratory discoveries with clinical applications (76). Although this study does not systematically incorporate clinical trial registration information, this omission does not have a substantial impact on the results of hotspot identification. The reason is that the research hotspots revealed by bibliometrics are rooted in the co-occurrence and clustering relationships of keywords in published academic papers, reflecting the accumulated knowledge in existing peer-reviewed literature. In contrast, clinical trial registration information is essentially a research plan or protocol, rather than publicly available scientific discoveries. Meanwhile, there is generally a time lag between the registration information and the final published results (77). Therefore, registration information is not suitable as a direct basis for identifying the current knowledge frontier, and its omission will not lead to the omission or bias of hotspot directions. Nevertheless, a comparative analysis of clinical trial registration information and bibliometric hotspots can still help verify the clinical relevance of basic research hotspots from the translational perspective. Therefore, it is recommended that future studies further integrate clinical trial registration data on the basis of bibliometric analysis to examine the connection between basic research hotspots and clinical translation.

Conclusions

This study conducted a thorough analysis of research development patterns in lung cancer and macrophage polarization by bibliometric methodologies. The results indicate that this field has shown a steady upward trend since 2010. China leads in the number of published papers, while the USA maintains its dominance in terms of academic influence. Journals like Frontiers in Immunology and International Immunopharmacology, which concentrate on the convergence of immunology and cancer, have emerged as significant venues for knowledge dissemination in this domain. The research focus has gradually evolved from the early exploration of the correlation between macrophage polarization phenotypes and pathological features of lung cancer to the in-depth analysis of the molecular mechanisms underlying macrophage polarization regulation. At present, the research has further extended to the clinical translation of nano-targeted delivery and immune checkpoint inhibitors. In the future, based on the existing foundation, it is necessary to thoroughly investigate the bottlenecks in the clinical implementation of targeted regulation strategies, optimize the construction of nano-carriers and combination drug regimens, and rely on the achievements of basic mechanism research to accelerate the transition of targeted regulation of macrophage polarization from laboratory research to clinical application in individualized immunotherapy for lung cancer.

Acknowledgments

All authors thank all individuals involved in the implementation, research, and evaluation of this study for their hard work and dedication; We acknowledge Qinjun Yang for valuable feedback during the preparation of this manuscript.

Footnote

Reporting Checklist: The authors have completed the BIBLIO reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0766/rc

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0766/prf

Funding: This study was supported by the Open Research Program of the Anhui Provincial Key Laboratory of Traditional Chinese Medicine Formulations (No. 2025AKLCMF04), the Anhui Provincial Higher Education Scientific Research Program (Natural Sciences) (No. 2022AH050492), and the 2022 Research Project for the Recruitment of High-Level Talent at Anhui University of Traditional Chinese Medicine (No. 2022rcyb012).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-0766/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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